DERIVATIVES OF 4a,9b-DIHYDRO-8,9b-DIMETHYL-DIBENZOFURAN-3(4H)-ONE

ABSTRACT

This disclosure describes derivatives of 4a,9b-dihdro-8,9bdimethyldibenzofuran and of 4a,9b-dihydro-8,9bdimethyldibenzofuran-3(4H)-one useful as intermediates or as analgetic agents.

United States Patent [1 1 MOt'lOCk et al.

[111 3,741,992 51 June 26, 1973 DERIVATIVES OF 4A,

[73] Assigneez. American Cyanamid'Coinpany,

Stamford, Conn.

{22] Filed: Nov. 23,1971 211 A No.: 201,515

' Related U.S. Application Data [62] Division of Ser. No. 34,519, May 4, 1970, Pat. No.

s2 fU.s.c|.. ..260/346.2M

511 m. c|.. con 5/34 58 Field of Seareh 260/3462 M [56] Relerenees; cued OTHER PUBLICATIONS Arkley et al., Chem. Abstracts (1957) vol. 5 l, 2717b.

Primary Examiner-Alex Mazel Assistant Examiner-Branrd Dentz I Attorney-Edward A. Conroy, Jr. I

'57 ABSTRACT This disclosure describes derivatives of 4a,9b-dihdro 8,9b-dimethyldibenzofuran and of 4a,9b-dihydro-8,9b-

dimethyldibenzofuran-3(4H)-one useful as intermediates or as a'nal'getic agents.

3 Claims, No Drawings DERIVATIVES OF 4A, 9B-DIIIYDRO-8,9B-DIMETI-IYL-DIBENZOFURAN 3(4H )-ONE CROSS REFERENCE TO RELATED APPLICATION This application isadivision of our copending application Ser. No. 34,5 19, filed May 4, l970 now US. Pat. 3,646,060.

BRIEF SUMMARY OF THE INVENTION This invention relates to novel derivatives of 4a,9b--

-dihydro-8,9b-dimethyldibenzofuran and of 4a,9b-

dihydro-8,9b--dimethyldiben zofurano-fs(4I-I)-one and to methods of preparing these compounds. The novel compounds of the present invention may be represented by the following general formulae:

wherein R is hydrogen, benzoyl or phenylcarbamoyl;

- R is hydrogen or o-brornobenzoyl; and R is phenyl or anilino.

DETAILED DESCRIPTION OF THE INVENTION (1956)] in accordance with the following reaction (Illa wherein each conversion is correlated with the corresponding specific example appended hereinafter;

Certainof the novelcompounds of the present invention (when R: is o-bromobenzoyl and'R is anilinolare active analgetics when measured by the writhing syndrome" test for analgetic activity as described by Siegmund et al., Proc. Soc. Exptl. Biol. Med., Vol.9, p. 729 (1957),with modifications. The method is based upon the reduction of the number of writhes following the intraperitoneal injection of l mg./kg. of body weight of phenyl-p-quinonc in male Swiss Albino mice wcighing 15-25 grams per mouse. The syndrome is characterized by intermittent contractions of the abdomen,

, twisting and turning of the trunk, and extension of the hind legs beginning 3 to 5 minutes after injection of the phenyl-p-quinone. The test compound is administered orally to groups of two mice each 30 minutes before in? jection of the phenyl-p-quinone. The total number of writhes exhibited by each group of mice is recorded for a 3 minute period commencing l5 minutes after injec-- tion of the phenyl-p-quinone. A compound'is considered active if it reduces the total number of writhes in two test mice from a control value of approximately 30 per pair to a value of 18 or less. In a representative op- Preparation eration, the compounds showed analgetic activity when tested by this procedure at the oral doses indicated in the following table:

Compound Oral dose mgJkg.

of body weight 4-benzoyl-4a,9b-dihydro-8 ,9b-di- 200 methyl-B-dibenzofuranyl o-bromobenzoate -3-oxo-2-dibenzofurancarboxanilide When mixed with suitable excipients or diluents, the above compounds can be prepared as pills, capsules, tablets, powders, solutions, suspensions, and the like for unit dosage and to simplify administration.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE I EXAMPLE [I of 4a,9b-dihydro-8,9b-dimethyl-3-(lpyrrolidinyl)-4-dibenzofuranyl phenyl ketone To a solution of 0.035 mole of l-(4a,9b-dihydro- 8,9b--dimethyl-3-dibenzofuranyl)pyrrolidine, prepared as in Example I, in 200 ml. of benzene was added 4.85 ml. (3.54 g. of triethylamine and then 4.00 ml. (4.92 g.) of benzoyl chloride. The resulting solution gradually became deep red in color and a gelatinous precipitate separated. The mixture was allowed to stand at room temperature for hours and then was filtered to remove 4.63 g. of triethylamine hydrochloride. Evaporation of the filtrate in vacuo yielded the crude productas a deep red syrup. One-half of this product was dissolved in benzene and chromatographed on 200 g. of neutral alumina (activity III). Elution with benzene and evaporation of the eluate yielded 3.27 g. of 4a,9bdihydro-8,9b-dimethyl-3-( l-pyrrolidinyl)-4- dibenzofuranyl phenyl ketone as a deep red syrup, A 3 6.10, 6.19, 6.30 and 6.40 ,u..

EXAMPLE lll Preparation of 2-benzoyl-4a,9b-dihydro-8,9bdimethyldibenzofuran-3(4H)-one To a solution of 0.816 g. of 4a,9b-dihydro-8,9bdimethyl-3-(1-pyrrolidinyl)-4-dibenzofuranyl phenyl ketone in 20 ml. ofmethanol was added 20 ml. of 0.1N hydrochloric acid" and then additional methanol was added to dissolve the precipitated oil. After being allowed to'stand for /2' hours at roomtemperature the mixture was filtered to yield 0.515 g. of crude product as a tan solid, mp, l50-160C. Recrystallization from absoluteethanol yielded 0.427 g. of 2-benzoyl-4a,9bdihydro-8,9b-dimethyldibenzofuran3(4H)-one as offwhite needles m.p. l65-l68C., A 5.95, 6.03,

4 6111 and a. Mm 250 nm 3,150 350 nm (1,860).

EXAMPLE lV Preparation of 4a,9b-dihydro-3-hydroxy-8,9bdimethyl-4-dibenzofuranyl phenyl ketone To a suspension of 0.156 g. of 2-benzoyl-4a,9bdihydro-8,9b-dimethyldibenzofuran-3(4H)-one in methanol and concentrated ammonium hydroxide was added chloroform until the solid was dissolved. The resulting two phase mixture was vigorously stirred for 3 "hours. The chloroform layerwas separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual yellow gum was triturated with-ether and the resulting suspension was filtered to remove 0.021 g. of starting material. The filtrate was evaporated to dryness under reduced pressure to yield 0.110 g. of 4a,9b-dihydro-3-hydroxy-8,9b-dimethyl-4- dibenzofuranyl phenyl ketone as a yellow solid, )t,,,,,,' g

5.90, 6.06, 6.28 and 6.34 A.

EXAMPLE V Preparation of dimethyl-3-dibenzofuranyl o-bromobenzoate To a solution of 0.00157 mole of 4a,9b-dihydro-3- hydroxy-8,9b-dimethyl-4-dibenzofuranyl phenyl ketone in 10 ml. of pyridine was added 0.345 g. of obromobenzoyl chloride. After 18 hours at room temperature the solution was evaporated under reduced pressure and the semi-solid residue was taken up in ether. The filtered solution was evaporated to dryness under reduced pressure to yield a yellow gum which was dissolved in benzene and chromatographed on 10 g. of alumina (activity 111). Evaporation of the benzene eluates and crystallization of the yellow residual gums gave 0.169 g. of 4-benzoyl-4a,9b-dihydro-S,9bdimethyl-3-dibenzofuranyl o-bromobenzoate as colorless crystal's, m.p.1l8-l22C., A 5.68, 6.02, 6.20 and 6.27 p" EXAMPLE Vl Preparation of 4a,9b-dihydro-8,9b-dimethyl-3-(lpyrrolidinyl)-4-dibenzofurancarboxanilide To 0.0221 mole of l-(4a,9b-dihydro-8,9b-dimethyl- 3-dibenzofuranyl)pyrrolidine, prepared as in Example I, in 100 ml. of dry benzene was added 2.4 ml. (2.64 g. of phenyl isocyanate and the solution was allowed to stand at room temperature for 20 hours. The mixture was filtered to yield, after washing with benzene, 2.50 g. of 4a,9b-dihydro-8,9b-dimethyl-3-( l-pyrollidinyl)-4- dibenzofurancarboxanilide as a yellow solid, m.p. l-177C., k 6.00, 6.10, 6.22 and 6.39 p.

EXAMPLE Vll Preparation of 3,4,4a,9a-tetrahydro-8,9b-dimethyl-3 oxo-2-dibenzofurancarboxanilide A suspension of 1.50 g. of 4a,9b-dihydr o-8,9b-' dimethyl-3-( l-pyrrolidinyl )-4-dibenzofurancarboxanilide in 100 ml. of methanol and 5 ml. of IN hydrochloric acid was refluxed with stirring for 4 hours. The cooled solution was evaporated to dryness under reduced pressure to yield a gum as residue. Trituration with water yielded a solid which was collected by filtration and recrystallized from ethanol to yield 0.801 g. of 3,4,- 4a,9a-tetrahydro-8,9b-dimethyl-3-oxo-2-dibenzofurancarboxanilide as colorless crystals, m.p. ll97C., mux' We claim:

1. A compound of the formula:

Q64 o\ CH3 wherein R3 is selected from-the group consistiiig of henyl and aniline.

7 jITlie bfiipoundaccording to Claim 1 wherein R3 is aniline; 3,4,4a,9a-tetrahydfo-8,9b-climethyl-3-oxo-2 dibenzofuran-carboxanilide. 

2. The compound according to Claim 1 wherein R3 is phenyl; 2-benzoyl-4a,9b-dihydro-8,9b-dimethyldibenzofuran-3(4H)--one.
 3. The compound according to Claim 1 wherein R3 is anilino; 3,4, 4a,9a-tetrahydro-8,9b-dimethyl-3-oxo-2-dibenzofuran-carboxanilide. 